Heart failure (HF) is a major public health problem in the United States. Although medical therapy can improve outcomes, data suggest that proven therapies continue to be underutilized. Current guidelines suggest that treatment be titrated toward the target doses used in clinical trials, but clinical inertia often represents a barrier to aggressive titration of medical therap for both providers and patients. There is a pressing need to develop strategies to improve the utilization of proven therapies for chronic HF in order to improve outcomes. The natriuretic peptides are biomarkers of hemodynamic stress that provide important prognostic information in HF. Changes in natriuretic peptide levels over time are strongly associated with outcomes, and HF therapies proven to have beneficial effects outcomes decrease natriuretic peptide levels over time. These data suggest that serial measurements of natriuretic peptides may serve as a guide to the titration of medical therapy in HF - biomarker guided therapy. Although small studies meta-analyses have suggested a decrease in mortality with this approach, there remains an unmet need for a robustly powered study to determine whether biomarker guided therapy improves outcomes in chronic HF. We propose to address this unmet need with the GUIDing Evidence Based Therapy Using Biomarker Intensified Treatment (GUIDE-IT) Study, a randomized clinical trial of biomarker guided therapy in HF. The primary aim of GUIDE-IT is to compare a strategy of medical therapy titrated to a natriuretic peptide target to usual care in 1100 high risk patients with HF. Our primary hypothesis is that biomarker guided therapy will reduce the composite endpoint of time to cardiovascular death or first HF hospitalization by 20% compared to usual care over a follow up period of at least 12 months. This application includes a Clinical Coordinating Center, a Data Coordinating Center, and an Economics-Quality of Life core lab. GUIDE-IT will test an innovative model of HF management-the individualized titration of medical therapy to a physiologic target rather than a one size fits all approach. Results of GUIDE-IT will be guideline changing and have immediate clinical implications for the management of millions of Americans living with chronic HF.